The present invention relates to a method for the preparation of the well known antidepressant drug citalopram, 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile.
Citalopram is a well-known antidepressant drug that has now been on the market for some to years and has the following structure: 
It is a selective, centrally acting serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, having antidepressant activities. The antidepressant activity of the compound has been reported in several publications, e.g. J. Hyttel, Prog. Neuro-Psychopharmacol. and Biol. Psychiat., 1982, 6, 277-295 and A. Gravem, Acta Psychiatry. Scand., 1987, 75, 478-486. The compound has also been disclosed to show effects in the treatment of dementia and cerebrovascular disorders, EP-A 474580.
Citalopram was first disclosed in DE 2,657,271 corresponding to U.S. Pat. No. 4,136,193. This patent publication describes the preparation of citalopram by one method and outlines a further method that may be used for preparing citalopram.
According to the process described, the corresponding 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile is reacted with 3-(N,N-dimethylamino)propyl-chloride in the presence of methylsulfinylmethide as condensing agent. The starting material was prepared from the corresponding 5-bromo derivative by reaction with cuprous cyanide.
According to the second method, which is only outlined in general terms, citalopram may be obtained by ring closure of the compound: 
in the presence of a dehydrating agent and subsequent exchange of the 5-bromo group with cyano using cuprous cyanide. The starting material of formula II is obtained from 5-bromophthalide by two successive Grignard reactions, i.e. with 4-fluorophenyl magnesium chloride and N,N-dimethylaminopropyl magnesium chloride, respectively.
A new and surprising method and an intermediate for the preparation of citalopram were described in U.S. Pat. No. 4,650,884 according to which an intermediate of the formula 
is subjected to a ring closure reaction by dehydration with strong sulfuric acid in order to obtain citalopram. The intermediate of formula III was prepared from 5-cyanophthalide by two successive Grignard reactions, i.e. with 4-fluorophenyl magnesium halogenide and N,N-dimethylaminopropyl magnesium halogenide, respectively.
Further processes are disclosed in International patent application Nos. WO 98/019511, WO 98/019512 and WO 98/019513. WO 98/019512 and WO 98/019513 relate to methods wherein a 5-amino-, 5-carboxy- or 5-(sec. aminocarbonyl)phthalide is subjected to two successive Grignard reactions, ring closure and conversion of the resulting 1,3-dihydroisobenzofuran derivative to the corresponding 5-cyano compound, i.e. citalopram. International patent application No. WO 98/019511 discloses a process for the manufacture of citalopram wherein a (4-substituted-2-hydroxymethylphenyl-(4-fluorphenyl)methanol compound is subjected to ring closure and the resulting 5-substituted 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran converted to the corresponding 5-cyano derivative and alkylated with a (3-dimethylamino)propylhalogenide in order to obtain citalopram.
Finally, methods of preparing the individual enantiomers of citalopram are disclosed in U.S. Pat. No. 4,943,590 from which it also appears that the ring closure of the intermediate of formula III may be carried out via a labile ester with a base.
It has now been found that citalopram may be obtained in a high yield as a very pure product by a new process in which an optionally substituted 2-[1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-yl]oxazoline or -thiazoline is converted in one step to citalopram substantially without any occurrence of undesired side-reactions.
It has also been found that it is possible to prepare the optionally substituted 2-[1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)- 1,3-dihydroisobenzofuran-5-yl]oxazoline or -thiazoline intermediate directly starting from 5-carboxyphthalide, by formation of its amide with an optionally substituted 2-hydroxy-ethylamine or 2-mercapto-ethylamine and ring closure. The intermediate oxazolines and thiazolines are stable under the Grignard reaction conditions.
Accordingly, the present invention relates to a novel method for the preparation of citalopram, its enantiomers and acid addition salts thereof comprising treatment of a compound of formula IV 
wherein X is O or S;
R1-R2 are each independently selected from hydrogen and C1-6 alkyl, or R1 and R2 together form a C2-5 alkylene chain thereby forming a spiro-ring; R3 is selected from hydrogen and C1-6 alkyl, R4 is selected from hydrogen, C1-6 alkyl, a carboxy group or a precursor group therefore, or R3 and R4 together form a C2-5 alkylene chain thereby forming a spiro-ring; with a dehydration agent or alternatively where X is S, thermally cleavage of the thiazoline ring or treatment with a radical initiator, such as peroxide or with light, to form citalopram having the formula 
as the base or an acid addition salt thereof, and thereafter optionally converting said base or said acid addition salt to a pharmaceutically acceptable salt thereof.
The dehydration agent may be any suitable dehydration agent conventionally used in the art, such as phosphoroxytrichloride, thionylchloride, phosphorpentachloride, PPA (polyphosphoric acid), and P4O10. The reaction may be carried out in the presence of an organic base, such as pyridine.
Alternatively, the dehydration agent may be a Vilsmeier reagent, i.e. a compound which is formed by reaction of a chlorinating agent, preferably an acid chloride, e.g. phosgene, oxalyl chloride, thionyl chloride, phosphoroxychloride, phosphorpentachloride, trichloromethyl chloroformate, also briefly referred to as xe2x80x9cdiphosgenexe2x80x9d, or bis(trichloromethyl) carbonate, also briefly referred to as xe2x80x9ctriphosgenexe2x80x9d, with a tertiary amide such as N,N-dimethylformamide or a N,N-dialkylalkanamide, e.g N,N-dimethylacetamide. A classic Vilsmeyer reagent is the chloromethylenedimethyliminium chloride. The Vilsmeier reagent is preferably prepared in situ by adding the chlorinating agent to a mixture containing the starting oxazoline or thiazoline derivative of formula IV and the tertiary amide.
When X is S and the conversion of the thiazoline group into the cyano group is made by thermal transformation, the thermal decomposition of compound IV is preferably carried out in an anhydrous organic solvent, more preferably an aprotic polar solvent, such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide or acetonitrile. The temperature at which the thermal decomposition transforms the 2-thiazolyl group to a cyano group is between 60xc2x0 C. and 140xc2x0 C. The thermal decomposition may conveniently be carried out by reflux in a suitable solvent, preferably acetonitrile. The thermal cleavage may conveniently be carried out in the presence of oxygen or an oxidation agent. Compounds of formula IV where X is S and R4 is a carboxy group or a precursor for a carboxy group can also be converted to citalopram by treatment with a radical initiator such as light or peroxides.
In a further aspect, the invention relates to the above process in which the compound of formula IV is in the form of the S-enantiomer.
In yet another aspect, the present invention relates to citalopram and S-citalopram manufactured by the process of the invention and an antidepressant pharmaceutical composition comprising citalopram or S-citalopram manufactured by the process of the invention.
According to the present invention, it has surprisingly been found that the oxazoline or thiazoline group may be introduced into the 5-position of phthalide and that remain stable during the subsequent reactions.
Furthermore, it has been found that the 1,1-disubstituted isobenzofurancarbonyl group in the intermediate of formula IV is surprisingly stable and that the reaction of the 2-[1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-yl]oxazoline or -thiazoline with a dehydration reagent, in particular by a Vilsmeier reagent, to give the corresponding nitrile, i.e. citalopram, may be carried out at higher temperatures than those described in relation to such dehydration reactions in the literature.
It has also been found that, due to the combined stability of the optionally substituted 2-oxazolinyl or 2-thiazolinyl group and the 1,1-disubstituted isobenzofuranyl group, it is possible to prepare the 2-[1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-yl]oxazoline or -thiazoline intermediate IV and, hence, citalopram and its salts in pure form, starting directly from 5-carboxyphthalide.
By the process of the invention, citalopram is obtained as a pure product in good yield thereby reducing costly purification processes.
According to the present invention, the compound of formula IV may be prepared from 5-carboxyphthalide and transformed to citalopram and its salts by a process, comprising:
a) reacting a functional derivative of 5-carboxyphthalide of formula V 
xe2x80x83with a 2-hydroxy- or 2-mercaptoethanamine of formula VI 
xe2x80x83in which X, R1-R4 are as defined above,
(b) submitting the amide of formula VII thus obtained 
xe2x80x83in which X, R1-R4 are as defined above, to a ring closure by dehydration;
(c) submitting the 2-(1-oxo-1,3-dihydroisobenzofuran-5-yl)oxazoline or -thiazoline of formula VIII thus obtained 
in which X, R1-R4 are as defined above, to two subsequent Grignard reactions, the first with a fluorophenyl magnesium halide and the second in situ with a [3-(dimethylamino)propyl]magnesium halide;
(d) submitting the 2-[3-hydroxymethyl-4-[(1-(4-fluorophenyl)-1-hydroxy-[4-(dimethylamino)butyl]phenyl]oxazoline of formula IX thus obtained 
xe2x80x83in which X, R1-R4 are as defined above, to a ring closure by dehydration;
(e) reacting the 2-[1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-yl]oxazoline or -thiazoline thus obtained of formula IV 
in which X, R1-R4 are as defined above, with a dehydration reagent or alternatively if X is S subjecting the compound of formula IV to a thermal decomposition reaction, or treatment with a radical initiator; and isolating the thus obtained citalopram in form of the free base or as an acid addition salt thereof; and
(f) optionally converting said free base or said acid addition salt to a pharmaceutically acceptable salt thereof.
The total synthesis of citalopram as outlined above, comprises the use of novel intermediates for the preparation of the intermediary oxazolines or thiazolines by reaction of a 5-carboxyphthalide with an optionally substituted etanolamine or mercaptoethylamine and ring closure of the amide thus obtained.
The functional derivative of 5-carboxyphthalide used in step (a) is a acid halide thereof, the anhydride, a mixed anhydride, an active ester, for example the 4-nitrophenylester, or the free acid, suitably activated for example with dicyclohexylcarbodiimide. A preferred functional derivative is the acid chloride, which may be obtained by reaction of the free acid with thionyl chloride and straightforwardly made to react in situ with the 2-hydroxy-ethylamine or 2-mercapto ethylamine of formula VI. The 5-carboxyphtalide can be prepared from 5-cyanophtalide.
Another advantageous functional derivative is the mixed anhydride with a monoester of carbonic acid, preferably with carbonic acid monoethylester, which may be obtained from 5-carboxyphthalide and ethyl chloroformate and directly made to react in situ with the 2-hydroxy-ethylamine or 2-mercapto ethylamine of formula VI.
In the starting material of formula VI, R1-R4 are preferably selected from methyl or ethyl or hydrogen or one of the pairs of R1 and R2 or R3 and R4, respectively, are linked in order to form a 1,4-butylene or a 1,5-pentylene group. Most preferably, R1 and R2 and R3 and R4, respectively, are identical. The preferred reagents are 2-amino-2-methyl-1-propanol, 2-amino-2-methyl-1-propanthiol, 2-amino-3-hydroxy-propionic acid (R,S-serine, R-serine, and S-serine) and R,S-cysteine, R-cysteine and S-cysteine. The compounds of formula VI are commercially available or may be prepared from commercially available compounds using conventional methods.
The reaction of the functional derivative of 5-carboxyphthalide (V) with the ethanolamine or mercaptoethylamine VI is carried at a temperature of 10-40xc2x0 C., preferably at 15-25xc2x0 C., in an aprotic organic solvent such as an ether, for example methyl t-butyl ether, tetrahydrofuran or dioxane, a ketone, for example acetone or methylisobutylketone, a hydrocarbon, for example toluene, or a chlorinated solvent, for example dichloromethane, 1,2-dichloroethane or 1,1,1-trichloroethane. Preferably, a hydrocarbon, conveniently toluene, is used when the functional derivative is the chloride, whereas a ketone, conveniently acetone, is used when the functional derivative is a mixed anhydride. The reaction occurs in the usual manner of formation of the amides. However, when the activated acid derivative is the 5-carboxy phthalide chloride, the reaction is conveniently carried out in the presence of an inorganic base such as sodium or potassium carbonate, whereas an organic base such as triethylamine may be employed when, for example, the mixed anhydride with carbonic acid monoethylester is used as functional derivative.
In step (b), the amide of formula VII is submitted to a ring closure reaction by dehydration, preferably by treatment with thionyl chloride. The amide of formula V is added to the dehydration agent at low temperature, namely at less than 10xc2x0 C., preferably less than 5xc2x0 C., most preferred between xe2x88x9210xc2x0 C. and 3xc2x0 C. When thionyl chloride is used, the temperature is advantageously less than 0xc2x0 C., preferably about xe2x88x9210xc2x0 C. Then the temperature is allowed to rise to 20xc2x0 C. and the reaction is completed at a temperature of 20-40xc2x0 C., preferably at 25-35xc2x0 C., most preferred at 28 to 30xc2x0 C.
When thionyl chloride is used as the dehydrating agent the 2-(1-oxo-1,3-dihydroisobenzofuran-5-yl)oxazoline or -thiazoline of formula VIII is obtained in the form of a hydrocloride which may be isolated by dilution with an etheric solvent, preferably tetrahydrofuran. The corresponding base may be isolated by precipitation from an aqueous alkaline solution of the hydrochloride.
The above steps (a) and (b) can be carried out as a one-pot process, namely without isolating the amide of formula VII.
In step (c), the compound of formula VIII thus obtained is submitted to two subsequent Grignard reactions. In particular, it is reacted under usual conditions with a 4-fluorophenyl magnesium halide, conveniently the chloride or the bromide, preferably the bromide, and preferably using tetrahydrofuran as solvent. The reaction mixture is then treated with a [3-(dimethylamino)propyl]magnesiumhalogenide, conveniently the chloride or bromide, preferably the chloride, dissolved in the same solvent used for the previous Grignard reaction, preferably tetrahydrofuran, using the usual conditions of a Grignard reaction.
The 2-[3-hydroxymethyl-4-[(1-(4-fluorophenyl)-1-hydroxy-[4-(dimethylamino)butyl]phenyl]oxazoline or -thiazoline of formula IX thus obtained may be isolated according to the conventional techniques.
In step (d), ring closure of compound IX is carried out through elimination of a molecule of water. This elimination may be effected by an acid or via a labile ester with a base. Acidic ring closure is performed with an inorganic acid, such as a sulfuric or phosphoric acid, or an organic acid, such as methylsulfonic, p-toluenesulfonic or trifluoroacetic acid. The basic ring closure is performed via a labile ester, such as the methane sulfonyl, p-toluene sulfonyl, 10-camphorsulfonyl, trifluoroacetyl or trifluoromethanesulfonyl ester in presence of a base, such as triethyl amine, dimethylaniline, pyridine, etc. The reaction is performed in an inert solvent, preferably with cooling, in particular about 0xc2x0 C. and is preferably carried out by a one-pot procedure, i.e. with esterification in presence of a base.
Step (e), the treatment of the compound of IV with the dehydrating reagent is carried out as described above. The reaction of the compound of formula IV, as the free base or as a salt thereof, with the Vilsmeier reagent is carried out in anhydrous organic solvent. The anhydrous organic solvent may be an apolar solvent such as a hydrocarbon, e.g toluene or xylene, or a polar solvent, or it may be the N,N-dimethylformamide or N,N-dimethylacetamide which form the Vilsmeier reagent, wherein the tertiary amide is present in at least the stoechiometrical amount in respect of the acid chloride, preferably in an excess thereof, e.g in a double amount of the stoechiometrical amount. Addition of the clorinating agent is generally made at low temperatures, but the reaction itself occurs at a temperature of from 80-150xc2x0 C., preferably 90-130xc2x0 C., or more preferred 100-120xc2x0 C. These temperature ranges allow the reaction to be completed within 4 hours, particularly within 30-60 minutes.
Ring closure in step d) and subsequent dehydration in order to convert oxazoline or thiazoline to CN in step e) may in a preferred embodiment be performed in one step without isolation of the intermediate of formula IV, e.g. by using thionylchloride as dehydration agent.
As set forth above, the citalopram thus obtained may be isolated in form of free base or of a salt thereof and converted to the selected final product, preferably citalopram hydrobromide.
The process of the present invention allows the preparation of citalopram and of its salts starting from compounds carrying an oxazoline or thiazoline groups which represent valuable and direct precursors of the cyano group which are stable under the conditions of a Grignard reaction. Thermal decomposition of the oxazoline or thiazoline groups in the compound of formula IV may be very simple and convenient.
Moreover, the process of the present invention allows the preparation of two the enantiomers of citalopram and of their salts starting from the corresponding enantiomers of the compound of formula IV or, when using the total synthesis starting from 5-carboxy phthalide, by resolution of the compound of formula IX. Compounds of formula IV or IX, in which R3 and R4 represent methyl and R1 and R2 are hydrogen, are particularly indicated.
The intermediates of formula IV and IX in the form of enantiomers, may be obtained using conventional separation techniques or as describe in U.S. Pat. No. 4.943.590.
It is advantageous to treat the compounds of formula IX as racemate, with an optically active acid, for example with (xe2x88x92)- or (+)-tartaric acid or (xe2x88x92)- or (+)-camphor-10-sulfonic acid, in order to separate the diastereoisomeric salt mixture and to isolate the optically active compound of formula IX, as free base or as a salt thereof.
The total synthesis of citalopram and of its salts directly from 5-carboxyphthalide, represents a preferred embodiment, and involves a series of intermediates which are a further object of the present invention.
Thus, according to another of its objects, the invention relates to the compounds of formula IV obtainable according to step (d) and the compounds of formula VIII and IX obtained according to step (b) and (c).
The salts of the compounds IV, VIII and IX may be any acid addition salt, including pharmaceutically acceptable acid addition salts, for example the hydrochloride, hydrobromide, hydrogen.
Other reaction conditions, solvents, etc. are conventional conditions for such reactions and may easily be determined by a person skilled in the art.
The compound of general formula I may be used as the free base or as a pharmaceutically acceptable acid addition salt thereof. As acid addition salts, such salts formed with organic or inorganic acids may be used. Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzene sulfonic and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.
The acid addition salts of the compounds may be prepared by methods known in the art. The base is reacted with either the calculated amount of acid in a water miscible solvent, such as acetone or ethanol, with subsequent isolation of the salt by concentration and cooling, or with an excess of the acid in a water immiscible solvent, such as ethylether, ethylacetate or dichloromethane, with the salt separating spontaneously.
The pharmaceutical compositions of the invention may be administered in any suitable way and in any suitable form, for example orally in the form of tablets, capsules, powders or syrups, or parenterally in the form of usual sterile solutions for injection.
The pharmaceutical formulations of the invention may be prepared by conventional methods in the art. For example, tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting maschine. Examples of adjuvants or diluents comprise: Corn starch, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvant or additive colourings, aroma, preservatives etc. may be used provided that they are compatible with the active ingredients.
Solutions for injections may be prepared by solving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to the desired volume, sterilisation of the solution and filling in suitable ampoules or vials. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, etc.
The invention is further illustrated by the following examples: